Thrombin is known to have a variety of activities in different cell types and thrombin receptors are known to be present in such cell types as human platelets, vascular smooth muscle cells, endothelial cells and fibroblasts. It is therefore expected that thrombin receptor antagonists will be useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role.
Thrombin receptor antagonists peptides have been identified based on structure-activity studies involving substitutions of amino acids on thrombin receptors. In Bernatowicz et al., J. Med. Chem., 39, p. 4879-4887 (1996), tetra- and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH2 and N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg-NH2. Peptide thrombin receptor anatgonists are also disclosed in WO 94/03479, published Feb. 17, 1994.
Himbacine, a piperidine alkaloid, has been identified as a muscarinic receptor antagonist. The total synthesis of (+)-himbacine is disclosed in Chackalamannil et al., J. Am. Chem Soc., 118, p. 9812-9813 (1996).
Thrombin receptor antagonists are known in the art. Examples of such compounds are disclosed in U.S. Pat. No. 6,063,847, herein incorporated by reference, Thrombin receptor antagonists are useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role.
Various process are described in the art to prepare himbacine analagoues. In addition to those disclosed in U.S. Pat. No. 6,063,847, other copending applications that describe processes to prepare himbacine analogues include U.S. patent application Ser. Nos. 11/331,324, 11/330,935, 11/330,936, and 11/330,521, all four applications filed on Jan. 12, 2006, and herein incorporated by reference. As illustrated below in Scheme VII, one of the processes disclosed in those applications employs the compound 3-(5-nitrocyclohex-1-enyl) acrylic acid (6) an intermediate in a process for the preparation of an orally bioavailable thrombin receptor antagonist (11). Each of copending U.S. patent application Ser. No. 11/331,324, (the '324 application) and Ser. No. 11/330,936 (the '936 application) also disclose processes utilizing 3-(5-nitrocyclohex-1-enyl) acrylic acid as an intermediate in the preparation of himbacine analogs. An example of one preparatory scheme is Scheme VII, below, described in the '324 application, which utilizes the acid (compound 6 in Scheme VII) in the provision of himbacine analog compound 11.

The '324 and '936 applications describe the preparation of 3-(5-nitrocyclohex-1-enyl) acrylic acid from acrolein and nitromethane, which is incorporated by reference herein. However the processes described entail many process steps and provide the acid in low yield and low purity, requiring additional steps to provide suitably pure material.
One possible approach to improved preparation of the acid intermediate is the isolation of the oxime analog of 3-(5-nitrocyclohex-1-enyl) acrylic acid (the compound of Formula IA, illustrated herein below) with subsequent oxidation of the oxime functional group to a nitro functional group.
Various reactions are known in the art to oxidize oximes to the corresponding nitro compound. For example, Olah, et al. in SYNLETT, pp 337-39 (April 1992) describe using sodium perborate in glacial acetic acid to form nitro compounds from the corresponding oxime. Emmons and Pagano, J. Am. Chem. Soc., 77, 4557-59 (1955), use peroxytrifluoroacetic acid as an oxidizing agent. Bose and Vanajatha use OXONE (potassium peroxymonosulfate) in acetonitrile to oxidize oximes to nitroalkanes (Synth. Commun., 28, 4531-4535 (1998)). Iffland and Yen in J. Am. Chem. Soc., 76, 4083-85 (1954) disclose using N-bromo-acetamide and zinc oxide to prepare nitroalkanes from the corresponding oxime. Other methods disclosed by Iffland are described in J. Am. Chem. Soc., 75, 4044-46 and 4047-4048 (1954) and J. Am. Chem. Soc., 75, 4083-85 (1954). Each of these oxidation processes are carried out using reagents and conditions which would oxidize other oxidation-sensitive groups present in the oxime, for example, unsaturated bonds, for example, carbon-carbon double bonds and carbon-carbon triple bonds. Accordingly, these methods would be unsuited to the provision of, for example, 3-(5-nitrocyclohex-1-enyl) acrylic acid by oxidation of the corresponding oxime.
Anionic molybdenum-peroxo complexes are known in the art to be effective oxidants for primary and secondary alcohols in nonpolar solvents. Bortolini et al., J. Org. Chem., 52, 5467-69 (1987). Ballistreri et al. in SYNLETT pp. 1093-4 (November 1996) describe the oxidation of alkyl oximes to the corresponding nitroalkanes by employing an Mo(VI) oxodiperoxo complex catalyst in acetonitrile, however, none of the compounds disclosed therein contained reactive functional groups other than the oxime substituent.
Tamami and Yeganeh in Eur. Polym. J. 35,1445-1450 (1999), describe two polymer supported anionic peroxomolybdenuym compound that can be used as oxidizing agents for a variety of organic compounds including oximes, however, they report that these reagents produce the corresponding aldehyde from the oxime.